1. Field of the Invention
The present invention relates to an intermediate useful for the synthesis of .beta.-lactam antibacterial agents of new-class and also to a process for producing the same.
2. Prior Art and Problems
It has recently been reported that a cephalosporin derivative having a formylamino group at the 7.alpha. position of the nucleus is found in a culture medium of Flavobacterium sp. SC12,154, which is one species of bacteria, and exhibits an antibacterial action. (The Journal of Antibiotics, Vol. 37, No. 7, pp. 773-780, 1984)
Also, according to recent disclosures, .beta.-lactam antibiotics of new-class having a formylamino group on the carbon atom adjacent to the carbonyl group of the .beta.-lactam ring have been chemically synthesized, and exhibit an antibacterial action for a large variety of gram-negative bacteria and gram-positive bacteria. (Japanese Patent Laid-open No. 38288/1983 and The Journal of Antibioitics, Vol. 39, p. 1788, 1986)
According to the literature cited above, .beta.-lactam antibiotics of new-class having a formylamino group are prepared by introducing an amino group onto the carbon atom adjacent to the carbonyl group of the .beta.-lactam ring and then formylating the amino group by a conventional method.
Therefore, in the production of these .beta.-lactam antibiotics of new-class having a formylamino group, a 7.alpha.-aminocephalosporin derivative represented by formula (A) below (for which the cephem nucleus is taken as an example) is an important intermediate, and the process for its production constitutes a problem. ##STR1## wherein R.sub.1 denotes a hydrogen atom or a group-A-B (where A denotes an oxygen atom or sulfur atom and B denotes (a) an acyl group, (b) a substituted or unsubstituted heterocyclic group containing as a ring member at least one kind of hetero-atom selected from the group consisting of oxygen atom, nitrogen atom, and sulfur atom, or (c) a substituted or unsubstituted carbamoyl group); R.sub.2 denotes a protective group of the hydroxyl group or carboxyl group; and R denotes an acylamino group or protected amino group.
There have already been disclosed the following processes for the production of the intermediate (A).
(i) Processes disclosed in U.S. Pat. No. 3,962,214 and U.K. Pat. No. 1,348,984.
According to one of these processes, the intermediate is prepared by reacting 7.beta.-acylamino-7.alpha.-alkyl- (or aryl-or benzyl-) thio-cephalosporin with anhydrous ammonia, an ammonium salt, or an amine in the presence of a heavy metal ion such as mercury, silver, thallium, lead, and copper ions.
According to another process, the intermediate is prepared by reacting 7.beta.-acylamino-7.alpha.-alkyl- (or aryl- or benzyl-) thio-cephalosporin with chlorine or bromine at a low temperature (produced by dry ice), thereby changing the 7.alpha.-side chain into a halosulfonium halide, and reacting the resulting compound with anhydrous ammonia, an ammonium salt, or an amine.
According to yet another process, the intermediate is prepared by oxidizing the 7.alpha.-side chain of 7.beta.-acylamino-7.alpha.-alkyl-(or aryl- or benzyl-) thio-cephalosporin into sulfoxide and reacting the resulting compound with anhydrous ammonia, an ammonium salt, or an amine.
The 7.beta.-acrylamino-7.alpha.-alkyl- (or alkyl- or benzyl-) thio-cephalosporin used as the starting material in the above-mentioned processes is produced from a 7-aminocephalosporin derivative by the steps of Schiff base formation, sulfenylation, cleavage of Schiff base, and acylation.
(ii) Process disclosed in Japanese Patent Laid-open No. 118789/1976.
According to this process, the intermediate is produced from 7.beta.-acylamino-7.alpha.-alkyl- (or aryl- or benzyl-) seleno-cephalosporin as the starting material by the same steps as in process (i) mentioned above.
The above-mentioned processes, however, would suffer from several disadvantages. For example, they use as the starting material a 7-substituted thio- (or seleno-) cephem compound which is synthesized by sulfenylation or selenylation which is performed under comparatively severe conditions; they employ a heavy metal salt or use a low temperature (about -80.degree. C.); and they need comparatively long steps and give the desired product in rather poor yields. Under these circumstances, there is a demand for a more convenient and commercially satisfactory process for introducing an amino group into the 7.alpha. position of the cephem ring.